Project Summary/Abstract Despite extensive research on the role of estrogens in breast cancer risk, little is known about the role of androgens, an important precursor to estrogen, in altering breast cancer susceptibility. Further, there is a critical need for etiologic investigation of the role of androgens in women and adolescent girls who are at higher risk of breast cancer from their family history of breast cancer. The proposed project will address this major gap in scientific evidence through an integrated program of training and research using longitudinal family-based cohorts to investigate the effect of dynamic androgen patterns on breast cancer risk across the lifecourse. Reproductive risk factors in breast cancer risk models (e.g., age at menarche, age at first birth, parity) are proxies for estrogen exposure, but such factors incompletely capture the hormonal environment, particularly androgen levels, which rise prior to puberty and are affected by other processes including stress. Some improvement in risk assessment has been seen using serum concentrations of single androgenic or estrogenic hormones. This proposal will investigate the full steroid hormone metabolome, including androgen, estrogen, progestagen and glucocorticoid metabolites, in relation to breast cancer risk. Measurement of androgens levels, as opposed to estrogens that vary more across the menstrual cycle, is more feasible in adolescents and pre-menopausal women and thus likely will be more useful in clinical risk assessment. Through use of ongoing family cohorts with existing biospecimens, we will investigate whether the magnitude of the associations between androgens and breast cancer risk and androgens and intermediate risk factors (puberty and menstrual cycle characteristics) differ in populations with high, intermediate and low underlying genetic susceptibility, a critical question for accurate risk assessment. Specifically, we will analyze data from two longitudinal studies enriched with girls and women with a family history of breast cancer, which represents underlying genetic susceptibility to cancer. The first is a prospective nested case-control study of women participating in the Prospective Family Study Cohort (n=75 cases, 150 controls from a cohort of 2,136 unaffected women). The second is the LEGACY Girls study, a multi-site cohort that enrolled 1040 girls ages 6- 13 years at baseline and has followed them semi-annually for the past six years. Analyses in these cohorts will include three key periods?adulthood, adolescence and childhood?to address specific hypotheses focusing on urinary androgen metabolites and breast cancer, puberty, body size, and early-life stress. We will use mobile health methods to track menstrual cycles in real time to better characterize hormone patterns. The proposed research will be complemented by experiential and didactic training in 1) family-based study design and risk assessment, 2) mechanistic- and trajectory-based analytics, 3) dissemination and implementation science. This research and training will launch a program of independent research on the genetic and biocultural factors shaping girls and women's hormone trajectories and breast cancer risk.